Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells
Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells
复制标题
伊曲康唑抑制 Hedgehog 信号通路从而诱导自噬介导的结肠癌细胞凋亡
DOI：
10.1038/s41419-020-02742-0
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发表时间：
2020-07-17
影响因子：
9
通讯作者：
Xu, Ronghua
中科院分区：
文献类型：
--
作者：
Deng, Huiming;Huang, Ling;Xu, Ronghua
伊曲康唑是一种抗真菌药物，用于治疗全身真菌感染。最近，据报道它通过抑制Hedgehog信号通路和血管生成而有效抑制肿瘤生长。在本研究中，我们研究伊曲康唑是否通过Hedgehog信号通路诱导结肠癌细胞自噬介导的细胞死亡。采用流式细胞术和TUNEL法检测结肠癌细胞株SW-480和HCT-116的细胞凋亡和细胞周期分布。免疫印迹法检测自噬和信号蛋白，免疫组化法检测细胞增殖相关抗原Ki-67。用激光扫描共聚焦显微镜和/或透射电镜观察自噬流和自噬体形成的图像。建立了结肠癌细胞异种移植小鼠模型。伊曲康唑处理通过G1期细胞周期阻滞以及SW-480和HCT-116结肠癌细胞的自噬介导的凋亡来抑制细胞增殖。此外，发现Hedgehog通路参与伊曲康唑介导的自噬的激活。使用Hedgehog激动剂重组人Sonic Hedgehog（rhshh）后，伊曲康唑可拮抗rhshh的激活。此外，用伊曲康唑治疗在携带HCT-116的小鼠中产生显著的癌症抑制。因此，伊曲康唑可能是一种潜在的治疗结肠癌的有效药物。
Itraconazole is as an antifungal medication used to treat systemic fungal infections. Recently, it has been reported to be effective in suppressing tumor growth by inhibiting the Hedgehog signaling pathway and angiogenesis. In the present study, we investigated whether itraconazole induces autophagy-mediated cell death of colon cancer cells through the Hedgehog signaling pathway. Cell apoptosis and cell cycle distribution of the colon cancer cell lines SW-480 and HCT-116 were detected by flow cytometry and terminal TUNEL assay. Autophagy and signal proteins were detected by western blotting and cell proliferation-associated antigen Ki-67 was measured using immunohistochemistry. The images of autophagy flux and formation of autophagosomes were observed by laser scanning confocal and/or transmission electron microscopy. Colon cancer cell xenograft mouse models were also established. Itraconazole treatment inhibited cell proliferation via G1 cell cycle arrest as well as autophagy-mediated apoptosis of SW-480 and HCT-116 colon cancer cells. In addition, the Hedgehog pathway was found to be involved in activation of itraconazole-mediated autophagy. After using the Hedgehog agonist recombinant human Sonic Hedgehog (rhshh), itraconazole could counteract the activation of rhshh. Moreover, treatment with itraconazole produced significant cancer inhibition in HCT-116-bearing mice. Thus, itraconazole may be a potential and effective therapy for the treatment of colon cancer.